Growing evidence suggests that injecting drug users (IDUs) and HIV+ IDUs exhibit abnormal neuroendocrinology such as limbic-hypothalamo-pituitary-adrenocortical (HPA) activity. Thus, the applicant's earlier investigations found attenuated norepinephrine (NE) and ACTH responses to a cold pressor challenge in HIV-1+ individuals. This raised the possibility that HIV-1 infection and IDU are associated with a lack of adaptation to "stressors." These abnormalities could also be mediators of mental disorders and negative medical outcomes in these populations. In order to develop strategies for suitable interventions, it is necessary to identify the HPA-specific neuroendocrine abnormalities in IDUs and HIV-1+ IDUs. This 5-year proposal investigates the responses of the HPA axis and autonomic system and their role as mediators in the pathogenesis of mental disorders including anxiety, depressed mood, distress and cognitive-motor dysfunctions in HIV-1+ IDUs. Two groups of IDUs (n=280), divided into HIV-1+ (n=140) and HIV-1- (n-140), and a group of non-IDUs and HIV-1- normal (non-IDU) individuals (n=140), will be investigated using a 2X3X3 cross-sectional design (men, women; African-American, Hispanics and Caucasians; HIV-1+ IDUs, HIV-1- IDUs and HIV-1- non-IDUs). HIV-1+ subjects will be recruited across the entire spectrum of infection. Subjects will be examined for symptoms of mental disorders using specific batteries and investigated for their neuroendocrine (ACTH, cortisol), and NE and E responses to cold pressor, star tracing and oCRH challenges, as well as expression of lymphocyte Type I and Type II corticosteroid receptor transcripts. Findings will be useful in explaining the pathogenesis of mental disorders occurring in HIV-1+ IDUs as well as in HIV-1- IDUs. Attempts will also be made to examine the role of plasma HIV-mRNA load (as well as blood CD4 cell counts) and that of HAART (highly active antiretroviral therapy) in HIV-1+ subjects since these drugs do not readily cross the blood-brain-barrier.